Our lab has classified outbred male Sprague-Dawley rats as either low or high cocaine responders (LCRs and HCRs, respectively) based on the median split of open field locomotor activity induced by an acute injection of low dose cocaine (10 mg/kg, i.p.). We have also shown that the LCR/HCR classification is predictive of differences in cocaine-induced locomotor sensitization, conditioned place preference, motivation to self-administer cocaine, [3H] dopamine (DA) uptake, and cocaine's ability to inhibit in vivo DA transporter (DAT) function. However, the cellular mechanisms underlying the observed differences between LCRs and HCRs remain unknown. I am interested in understanding these mechanisms and relating them to the behavioral differences. One explanation for the observed differences in cocaine activation and sensitization is that cocaine-induced regulation of DAT number and/or cocaine's affinity for DAT may differ between LCRs and HCRs. Another is that levels of extracellular DA may differ between LCRs and HCRs following acute and/or repeated cocaine. Aim 1: Determine the effect of acute and repeated cocaine on brain regional DAT number and cocaine's binding affinity for DAT in LCRs and HCRs. Aim 2: Determine basal and cocaine-induced changes in locomotor activity and extracellular DA in nucleus accumbens and dorsal striatum in freely behaving LCRs and HCRs. I propose to use locomotor activity, in vitro radioligand binding/quantitative autoradiography, and in vivo microdialysis to test the hypotheses that differences in DAT number, cocaine's binding affinity for DAT, and/or extracellular DA levels contribute to the LCR/HCR differences. My findings should provide important new insights into the mechanisms underlying the unique behavioral differences observed in LCRs and HCRs following cocaine administration. PUBLIC HEALTH RELEVANCE: The underlying mechanisms that mediate the progression from cocaine use to cocaine addiction are still being delineated. Animal models of individual differences in cocaine responsiveness may help us understand this important transition. My proposed studies will contribute to our understanding of how interactions between cocaine, the DAT, and DA are translated into differential cocaine activation - links that may both lead to future research for effective treatments for cocaine addiction, as well as shed light on the individual variability seen in humans in the progression from cocaine use to cocaine abuse.